Figure 2.

Theoretical concept of combined application of checkpoint blockade therapy and DGK-inhibition. (A) Functional unresponsiveness of TILs in the tumor milieu may have different mutually non-exclusive causes: (i) Ligation of PD-1 on T cells by tumor expressed PD-L1 may cause recruitment of phosphatase SHP2 and subsequent dephosphorylation of the TCR proximal signal transmitter Lck as well as attenuation of AKT-signaling. Consequently, signals initiated by TCR-peptide/MHC recognition intended to activate T-cell effector function (degranulation leading to lysis of target cells as well as IFNγ) are interrupted. The signal interruption through PD-1/PD-L1 classically occurs as a consequence of T-cell exhaustion. (ii) Anergy is another mechanism of T-cell silencing. The underlying cause is upregulated diacylglycerol kinase (DGK), in T cells mainly DGK-α and DGK-ζ. DGKs metabolize diacylglycerol (DAG) to phosphatidic acid (PA) lowering DAG levels which are necessary to activate TCR distal signaling through Ras/ERK. The ERK pathway is critically import for the degranulation process that delivers lytic proteins into the target cell for target cell death. (B) De-blocking the exhaustion pathway through checkpoint antibodies (anti-PD-1/PD-L1) releases the proximal brake at the TCR-associated molecules (Lck- and AKT-phosphorylation); however, distal brakes through DGK may still be active (blocked ERK pathway and attenuated PKC- and NFκB-activation) preventing full activation of the T cell‘s antitumor functions (degranulation, IFNγ). (C) Combined treatment with checkpoint antibodies and DGK-inhibitor may be required to open the signaling cascade fully, allowing effector function.